Sporadic inclusion body myositis (sIBM) is the most common acquired muscle disease associated with aging. sIBM afflicts individuals older than 50 years of age. While muscle weakness develops gradually, the disease is relentlessly progressive, leading to gross atrophy and severe weakness of both the distal and proximal muscles. Afflicted individuals are wheelchair bound within 5-10 years of onset. Pathologic analyses of patient muscle biopsies reveal two pathologies: (1) infiltration of inflammatory cells and (2) muscle degenerative changes consisting of rimmed vacuole formation, protein aggregate inclusions, and myonuclear breakdown. Despite this knowledge, the exact pathogenic cascade that leads to muscle degeneration and muscle weakness is poorly understood. Furthermore, the relationship between the inflammatory and degenerative components of sIBM remains a mystery. As a result, no effective treatment for sIBM exists. Dysregulation of sialic acid biosynthesis is implicated in inclusion body myopathy (IBM) pathogenesis. Mutations in UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase gene (GNE), which encodes the enzyme that catalyzes the first committed step of sialic acid biosynthesis, have been found in patients suffering from hereditary inclusion body myopathy (hIBM), an autosomal recesive disease. The pathology of hIBM mimics sIBM. Additionally, like sIBM, hIBM is a disease of aging;despite having a mutant gene at birth, humans harboring hIBM mutations in GNE do not develop muscle weakness until they reach a certain age, typically their mid-20s. Understanding how mutations in GNE and subsequent disruption of sialic acid homeostasis affects transcriptional and signaling networks will provide insight into pathways dysregulated in IBM. Aim 1 of this proposal is to ascertain the ability of sialic acid to act as a signaling molecule. This will reveal pathways dysregulated in IBM muscle. Aim 2 is to determine the sialic acid metabolite(s) that is acting as a signaling molecule and to discover the protein that is acting as a sialic acid sensor. The results of this work will reveal new therapeutic targets for IBM disease. The purpose of aim 3 is to determine the dependence of sialic acid signaling on subcellular localization. Taken together, these experiments will reveal novel roles for sugar metabolism and provide mechanistic insight into IBM, a common, devastating disease. PUBLIC HEALTH RELEVANCE: Sporadic inclusion body myositis is a relentlessy progressive muscle disorder that leads to severe weakness and it is the most common acquired muscle disease associated with aging. Dysregulation of a unique sugar, sialic acid, is implicated in hereditary forms of this disease. I will perform experiments to understand how sialic acid affects signaling and transcriptional networks which when disturbed would lead to disease.